1. Field of the Invention
The present invention relates to new pharmaceutical compounds having useful anti-spasmodic properties.
2. Description of the Prior Art
The purpose of an anti-spasmodic drug is to relieve spasms of the smooth muscles. Smooth muscles line most of the visceral organs. The peristalsis and muscular activity of the stomach, intestines, gall bladder, urinary bladder, lung, the uterus, and to a degree the heart are all largely controlled by smooth muscles. Smooth muscles are innervated by the autonomic nervous system. The autonomic nervous system consists of two antagonistic branches--the sympathetic branch and the parasympathetic branch. On all visceral organs except the heart the parasympathetic nerve impulses increase the irritability and tension of the smooth muscles; contrariwise, the sympathetic nerve impulses increase the tension and irritability of the muscles of the heart muscle and relax the smooth muscles of the other visceral organs.
A spasm in a smooth muscle may be due to one of two causes. Either the smooth muscle may be receiving exaggerated impulses from the autonomic nervous system which create violent contractions in the muscle, or the muscle may be intrinsically stimulated into a spasm (most likely from chemical changes in the surrounding tissue). A spasm due to exaggerated impulses from the parasympathetic branch of the autonomic nervous system may often be corrected by administering atropine (an active alkaloid of belladonna, which serves to break a connection between the parasympathetic nerve and the smooth muscle. This ability and effect of atropine is called a "neurotropic effect". A spasm intrinsic in the smooth muscle itself may often be corrected by papaverine (a derivative of opium which is classed as a narcotic). Papaverine has an ability to decrease intrinsically the contractility of smooth muscle; it has the ability to relax smooth muscles directly. This ability and effect of papaverine is called a "musculotropic effect."
In relieving spasms of smooth muscles generally, a musculotropic effect is acknowledged to be superior to a neurotropic effect. A neurotropic effect cannot relieve spasms intrinsic in the smooth muscle itself, while a musculotropic effect, by relaxing and decreasing the irritability and responsiveness of smooth muscle to stimulation from the autonomic nervous system, can help to relieve a smooth muscle spasm even when it is due to exaggerated impulses from the autonomic nervous system.
Atropine produces undesirable side-reactions which presents a clinical difficulty. Atropine when given in effective doses, serves to break or partly break all the parasympathetic nerve-smooth muscle connections throughout the body. Thus when atropine is given in sufficient dosage to relieve a spasm in a specific visceral organ, such as a gastric or intestinal spasm (the spasm caused by exaggerated nerve impulses from the parasympathetic nervous system) undesirable side-actions due to the breaking of the parasympathetic nerve-muscle connections elsewhere in the body may occur. The most easily recognized of these undesirable side reactions are dilation of the pupil and dryness of the mouth, caused by the breaking of the parasympathetic connections to the iris and the saliva producing mechanism respectively.
Atropine is acknowledged to have also a musculotropic effect, but its neurotropic effect is so strong that atropine must be given in minute doses not exceeding (1/60 to 1/40 grain). A dosage of 1/6 to 1/40 of a grain is too small to permit a significant musculotropic effect and when larger doses are administered undesirable side reactions are encountered.
U.S. Pat. No. 2,390,555 discloses a class of compounds comprising di-N-substituted aminoethyl esters of diphenylthioacetic acid of the general formula (C.sub.6 H.sub.5).sub.2 --CH--COS--CH.sub.2 CH.sub.2 --R in which R represents a disubstituted amino radical of either the diethylamino group, the morpholino group or the piperidino group with N as the point of attachment. This patent discloses that the thio analogs of certain disubstituted acetic acid esters of aminoalcohols have desirable anti-spasmodic properties. These compounds have proven to be very effective and are widely used as anti-spasmodics without encountering the undesirable side reactions due to excessive neurotropic effect.
U.S. Pat. No. 4,432,977 discloses new uses, especially for the dilation of the smooth muscles of the upper urinary tract, of the compounds disclosed in U.S. Pat. No. 2,390,555.
In Compte Rendu de la Societe de Biologie, 140, pp 477-9, (1946) Dupre, Levy and Tchoubar disclose a series of compounds having the formula C.sub.6 H.sub.5 (R)CH--C(O)--S--CH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2 where R is either a phenyl group, a propyl group, an isopropyl group, a butyl group or an isoamyl group. These compounds are all disclosed as being spasmolytic agents.
Compounds of the same general formula given above are disclosed by Tchoubar and Letellier-Dupre in Bulletin de la Societe Chimique, pp 792-4 (1947) wherein R was a phenyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isoamyl group or hydrogen.
In Farmakol. i. Toksikol., pp 10-17 (1956), Liberman discloses a class of compounds having the general formula (C.sub.6 H.sub.5).sub.2 CHCOSCH.sub.2 CH.sub.2 N--R.sub.2, wherein both R's are the same and are selected from methyl, ethyl, propyl and butyl groups; and a class of compounds having the general formula (C.sub.6 H.sub.5)--CH(C.sub.6 H.sub.11)COSCH.sub.2 CH.sub.2 N--R.sub.2, wherein both R's are the same and are selected from methyl, ethyl, propyl and butyl groups.
C. A. Buehler et al. in the Journal of Medicinal Chemistry, 6, pp 230-3 (1963) disclose physiologically active compounds of the general formula RR'C(OH)COS(CH.sub.2).sub.x NR.sub.2 ".HCl wherein R and R' are aryl groups, x is 2 or 3, and R.sub.2 " is a methyl or ethyl group.
R. O. Clinton et al. in the Journal of the American Chemical Society, 68, pp 2076-7 (1946) disclose synthesis of a number of dialkyl aminoalkyl diarylthiolacetates including fluorene-9-carbothioic acid, S-[2-diethylaminoethyl]ester.